Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions

嗅觉受体 mRNA 作为调节基因组相互作用的 lncRNA

• 批准号: 10614532
• 负责人: Stavros Lomvardas
• 金额: $ 48.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614532
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Affect; Alleles; Architecture; Binding; Binding Proteins; Biochemical; Chromatin; Chromosome Structures; Code; Complex; Data; Development; Developmental Process; Enhancers; Environment; Epigenetic Process; Experimental Genetics; Feedback; Gene Cluster; Gene Expression; Gene Family; Generations; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomics; Greek; Human; In Situ; Island; Light; Link; Mediating; Messenger RNA; Molecular; Mus; Neurodevelopmental Disorder; Neuronal Differentiation; Nuclear; Nuclear Proteins; Olfactory Pathways; Other Genetics; Phase; Phase Transition; Process; Production; Property; Proteins; RNA; RNA-Binding Proteins; Receptor Gene; Regulation; Regulator Genes; Reporting; Repression; Role; Signal Transduction; Specificity; Structure; System; Transcriptional Regulation; Untranslated RNA; Yeasts; experimental study; gene translocation; genetic approach; genomic locus; in vivo; insight; interdisciplinary approach; nerve stem cell; novel; olfactory receptor; olfactory sensory neurons; programs; promoter; receptor expression; recruit; transcription factor

Abstract The monogenic, monoallelic, and seemingly stochastic transcriptional choice of one out of > 1000 olfactory receptor (OR) genes remained elusive for decades after the discovery of the largest mammalian gene family. However, in the past few years we obtained significant understanding on the molecular underpinnings of this enigmatic gene regulatory process. Specifically, we showed that OR gene clusters become heterochromatic at the early stages of olfactory sensory neuron (OSN) differentiation and then they aggregate in distinct nuclear compartments that assure their stable repression. As a result of this interchromosomal convergence, intergenic OR enhancers (known as Greek Islands) that are found in most OR gene clusters come in close nuclear proximity and form a multi-chromosomal super-enhancer that in each OSN associates with the transcriptionally active OR allele. The formation of the Greek Island hub is dependent upon the recruitment of the adaptor protein Ldb1, which is essential for the stable interchromosomal interactions between Greek Islands and for OR transcription. This intricate network of activating and repressive interchromosomal interactions, together with a feedback signal elicited by the expression of the chosen OR, likely generate the regulatory framework for transcriptional singularity. However, what remains unknown is the process by which an OR allele is recruited to the Greek Island hub and the mechanism that assures that only one OR allele will remain stably associated with a multi-chromosomal structure that contains numerous enhancer elements. Our preliminary data suggest that developmentally transient OR transcription and production of nascent OR mRNAs contribute to the recruitment of an OR allele to the Greek Island hub and to OR gene choice. Thus, we propose genetic experiments that will determine which sequences of the sense OR mRNA are required and sufficient for recruitment of trans OR enhancers, what proteins recognized the nascent OR mRNA and what contribution these proteins have to the assembly of a multi-enhancer/OR complex. These experiments not only will shed light to the enigmatic process of OR gene choice, but will also provide general molecular principles for the mechanisms that mediate genomic compartmentalization during cellular differentiation.

抽象的 > 1000 个嗅觉中的一个的单基因、单等位基因和看似随机的转录选择 在发现最大的哺乳动物基因家族后的几十年里，受体（OR）基因仍然难以捉摸。 然而，在过去的几年里，我们对这种现象的分子基础有了重要的了解。 神秘的基因调控过程。具体来说，我们表明 OR 基因簇在以下位置变得异色： 嗅觉感觉神经元 (OSN) 分化的早期阶段，然后它们聚集在不同的核中 确保其稳定抑制的隔间。由于这种染色体间趋同，基因间 在大多数 OR 基因簇中发现的 OR 增强子（称为希腊群岛）都位于紧密的核中 接近并形成多染色体超级增强子，在每个 OSN 中与转录相关 活性或等位基因。希腊岛屿枢纽的形成取决于适配器的招募 蛋白质 Ldb1，对于希腊群岛之间稳定的染色体间相互作用至关重要 或转录。这种激活和抑制染色体间相互作用的复杂网络一起 通过所选 OR 的表达引发的反馈信号，可能会生成监管框架 对于转录奇异性。然而，仍然未知的是 OR 等位基因的形成过程 招募到希腊岛中心和确保只有一个 OR 等位基因保持稳定的机制 与包含许多增强子元件的多染色体结构相关。我们的初步 数据表明，发育瞬时 OR 转录和新生 OR mRNA 的产生有助于 向希腊岛中心招募 OR 等位基因以及 OR 基因选择。因此，我们提出遗传 实验将确定正义或 mRNA 的哪些序列是必需的并且足以 反式 OR 增强子的招募，哪些蛋白质识别新生 OR mRNA 以及有何贡献 这些蛋白质必须组装成多增强子/OR复合物。这些实验不仅会脱落 阐明 OR 基因选择的神秘过程，但也将为 OR 基因选择提供一般分子原理 在细胞分化过程中介导基因组区室化的机制。